Effect of Ketoconazole on the Pharmacokinetic Profile of Buprenorphine following Administration of a Once-Weekly Buprenorphine Transdermal System
| Autor: | Peter J. Perrino, Sarah A. O’Keefe, Salvatore V. Colucci, Stephen C. Harris, Alessandra Cipriano, Ram P. Kapil, Gregory Michels, Robert J. Noveck, Manjunath S. Shet |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Adult
Adolescent Cmax Pharmacology Placebo Administration Cutaneous Placebos chemistry.chemical_compound Young Adult Pharmacokinetics Double-Blind Method medicine Humans Pharmacology (medical) Norbuprenorphine Cross-Over Studies business.industry General Medicine Middle Aged Crossover study Erythromycin breath test Buprenorphine Ketoconazole chemistry Breath Tests Anesthesia Area Under Curve business medicine.drug |
| Zdroj: | Clinical Drug Investigation. 32:583-592 |
| ISSN: | 1173-2563 |
| DOI: | 10.2165/11633060-000000000-00000 |
| Popis: | Background and Objective: Buprenorphine is extensively metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the effect of ketoconazole, a CYP3A4 inhibitor, on the metabolism of buprenorphine following the administration of a buprenorphine transdermal system 10μg/hour (BTDS 10). Methods: This single-centre study enrolled 20 healthy subjects who had demonstrated ketoconazole-mediated CYP3A4 inhibition via an erythromycin breath test. Subjects were randomized into a placebo-controlled, two-treatment, two-period crossover study. Subjects participated in a 7- to 14-day screening period, two baseline evaluations (day 0 [period 1] and day 16 [period 2]), two 12-day treatment periods (periods 1 and 2) separated by a 4-day washout period, and a study completion visit. Subjects received one BTDS 10 for 7 days per treatment period, administered concomitantly with either ketoconazole 200 mg twice daily or matching placebo. The main outcome measures were the ratios of geometric means for area under the plasma drug concentration versus time curve (AUC) from time zero to time of last measurable concentration (AUClast), AUC from time zero to infinity (AUC∞), and maximum plasma drug concentration (Cmax). Results: The ratio of geometric means (BTDS 10 with ketoconazole/BTDS 10 with placebo) was 99.4 (90% confidence interval [CI] 87.2, 113.3) for AUClast and 97.8 (90% CI 87.7, 109.1) for Cmax. The ratio of geometric means for AUC∞ was 86.7 (90% CI 70.7, 106.2). The plasma concentrations of the metabolites norbuprenorphine and norbuprenorphine-3β-glucuronide were slightly elevated following ketoconazole administration. BTDS 10 with ketoconazole was well tolerated and no apparent safety concerns were noted. Conclusion: The lack of a clinically significant CYP3A4 interaction with ketoconazole following transdermal delivery of buprenorphine is consistent with the parenteral administration of a high clearance drug bypassing exposure to gut wall and hepatic CYP3A4 first-pass effects. Metabolism of buprenorphine during therapy with BTDS is also not expected to be affected by co-administration of other CYP3A4 inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|